Nuclear magnetic resonance investigation of the interaction of water vapor with sildenafil citrate in the solid state

Synthesis and Characterization of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Propoxybenzoates and Their Hydrochloride Salts

“…60 ppm was attributed to N22 sites. Moreover, this assignment is in good agreement with the previously published data for piperazine analogues (sildenafil citrate, [15]). …”

“…60 ppm was attributed to N22 sites. Moreover, this assignment is in good agreement with the previously published data for piperazine analogues (sildenafil citrate, [15]). The recorded 13 C-and 15 N-CP/MAS NMR spectra, in the majority of which splitting and asymmetric broadening of signals is apparent, reflect the extensive conformation variability of the investigated compounds; see Figures 2 and 3.…”

“…As indicted by the quantum-chemical calculations demonstrated in Figure 1, the protonation of an -N-site in the piperazine ring leads to a decrease in the 15 N resonance frequencies of both nitrogen sites, regardless which one of them is directly protonated. The calculated changes in 15 N resonance frequencies are in very good qualitative agreement with the experimental data obtained for base form 3e and monohydrochloride form 4e; see Figure 1. However, to verify the protonation of both nitrogen sites and/or to site-specifically locate the position of H + ion, we assessed the strength of 1 H-15 N dipolar couplings for each resolved nitrogen site by using the CPPI experiment [17][18][19] with a variable polarization-inversion (PI) period.…”

“…A slightly more complex splitting of 13 C-CP/MAS NMR signals of methyl and methylene units (C35, C34) indicates the slight conformation disorder of propyl substituents in crystals of 4a (R = H), 4b (R = 2-F) and 4d (R = 2-OCH 3 ) compounds. As reflected by single lines detected in the corresponding 15 N-CP/MAS NMR spectra, the local structure in the vicinity of nitrogen atoms is nearly unaffected by this local disorder and remains uniform in the whole crystal structure. As demonstrated by multiple splitting of signals in 13 C-and 15 N-CP/MAS NMR spectra, the most complex crystal structures can be expected for final monohydrochloride 4e (R = 4-OCH 3 , prepared by the equimolar amount of HCl) and sample 5e (R = 4-OCH 3 ) prepared from base 3e with excess of HCl.…”

“…In solid state, the assignment of 15 N-NMR signals is generally complicated by the extremely low sensitivity of 1 H-15 N heteronuclear correlation (HETCOR) NMR experiments. This is due to the combination of many factors, among which slow 1 H spin-lattice relaxation, signal broadening caused by static disorder and large chemical shift anisotropy inducing the formation of intensive spinning side bands play major roles.…”